Prostate cancer (CaP) is the most frequently diagnosed cancer and the second cause of cancer deaths in men in the US. Four potent anti-cancer activities have been ascribed to Vitamin D: 1) anti-proliferation, 2) anti-angiogenesis, 3) pro-apoptosis and 4) pro-differentiation. However, vitamin D also mobilizes calcium stores causing toxic hypercalcemic effects. New analogs have been developed that retain the anti-cancer activities of vitamin D but without the associated systemic toxicity. Our hypothesis is that vitamin D compounds, that retain anti-cancer properties but have reduced calcemic activity, can be used as a chemopreventive agent to prevent/slow the progression and metastatic spread of CaP. We propose 4 specific aims: I: To determine if calcitriol and two vitamin D analogs with low systemic toxicity (1LX23-7553 & QW1624F2-2) can prevent/slow carcinogenesis in an autochthonous model of CaP (TRAMP) and characterize the molecular effects of these compounds during prostate cancer progression. II: To determine if calcitriol and the less calcemic vitamin D compounds ILX23-7553 & QW1624F2-2 can prevent/slow the development and metastatic spread of androgen-independent CaP in castrated TRAMP animals and characterize the molecular effects of these compounds on androgen-independent disease. III: To identify key molecular pathways involved in vitamin D?s anti-cancer activity by comparing the molecular phenotype of tumor-derived cells from naive TRAMP tumors and vitamin D-resistant TRAMP tumors. IV: To evaluate the in vivo response of human CaP to ILX23-7553 by treating men with localized CaP prior to prostatectomy with ILX23-7553 and characterizing the molecular phenotype of the response. Effects of calcitriol, ILX23-7553 and QWI1624F2-2 treatment on proliferation, apoptosis, angiogenesis and differentiation will be studied in androgen-dependent and -independent CaP. Vitamin D resistant tumors will be induced in TRAMP and the molecular phenotype compared to naive TRAMP tumors. Finally a clinical trial examining the in vivo molecular response of organ confined human CaP to ILX23-7553 is proposed. These studies will provide preclinical data on the preventive activity of vitamin D compounds that can be used to design and initiate clinical trials using these compounds as a chemopreventive agent for human prostate cancer. These studies will identify key molecular pathways for vitamin D action that can be used to identify patients that are most/least likely to benefit from vitamin D therapy.